Friedreich's Ataxia

Last edited on May 1, 2011 by Timothy C. Hain, MD, Chicago IL.

Friedreich's ataxia (FA) was thought to be the most common inherited ataxia, before FXTAS was discovered. Friedreichs is transmitted with autosomal recessive inheritance. It's estimated prevalence in European populations is 1 in 50,000. It is associated with a mutation that consists of unstable expansion of GAA repeats on chromosome 9. The repeat expansion causes a transcriptional defect of the fratxin gene, a small mitochondrial protein, that is responsible for all of the clinical manifestations of FA.

Considering all cases of inherited ataxia, FA alleles were found in about 11.4% of apparently recessive and 5.2% of apparently sporadic patients (Moseley et al, 1998).

Clinical picture:

Onset of symptoms is usually before 20 years of age (15 +- 8). There is ataxia of all four limbs associated with cerebellar dysarthria, absent reflexes in the lower limbs, sensory loss and pyramidal signs. Hypertrophic concentric cardiomyopathy is found in a majority of patients. Skeletal deformities and abnormalities in glucose metabolism are common. Other associated findings may be facial dysmorphia, myoclonus, dystonia, postural tremor, supranuclear gaze paresis, and mental retardation.

Abnormal auditory evoked responses are found in about 50% of patients, and the auditory neuropathy syndrome has been reported in this disease. Sensorineural hearing loss may occur.

Prognosis

In patients homozygous for GAA expansion, the mean time to wheelchair confinement averages 10.8 years, and the mean disease duration is 15+-9 years. (Cosee et al, 1999). Death often occurs due to the cardiomyopathy.

Pathology:

The pathology of FA is largely confined to the dorsal root ganglion. Cerebellar neurons are usually normal but there are also lesions in the dentate nucleus. There are also effects on the heart, skeleton and endocrine pancreas. Temporal bones from patients with Freidreichs have shown spiral ganglion and Scarpa's ganglion cell degeneration (Merchant et al, 2001).   About 2/3 of patients have a cardiomyopathy, and most patients eventually succumb to it (Bidichandani et al, 1993). Many become diabetic during their life (Koeppen AH, 2011).

Treatment:

Little treatment is available other than supportive care, but there are a few trials

• Idebenone has been tried extensively in FA.  Small improvements have been reported, although no studies have reported a significant improvement. (Mariotti et al, 2003; Lynch et al, 2010).
• Combination treatment with Idebenone and deferiprone was reported helpful in 20 patients with FA (Velasco-Sanchez et al, 2011).

Current thought is that there is no agent that has a significantly positive effect.

Genetics

The following is just a brief discussion of how autosomal recessive inheritance works.  It is not meant to substitute for genetic counseling.

FA is almost always a autosomal recessive disease. Generally speaking then, all children of persons with FA are FA carriers. They cannot develop FA themselves as long as their their other parrent is not also a carrier. As the frequency of FA is 1/50,000 in the general population, the chance of encountering another carrier in a spouse is roughly 1/200. When a homozygote for a recessive disorder marries a carrier, the chance of children being affected is 50%. Thus, the chance that a person with FA's children will also have FA is about 1/400.

Should two carriers marry, there is a 25% chance that a child will be affected, a 50% chance that the child will be a carrier, and a 25% chance that the child will not carry the mutation at all. (Bidichandani and Delatycki 1993)

Siblings of a person with FA have a 25% chance themselves of having FA, a 50% chance of being a carrier, and a 25% chance of having no mutation.

References

• Bidichandani, S. I. and M. B. Delatycki (1993). "Friedreich Ataxia."
• Cosee M and many others. Friedreichs ataxia: point mutations and clinical presentations of compound heterozygotes. Ann Neurol 1999:45:200-206
• De Pablos C, Berciano J, Calleja J. Brain stem auditory evoked potentials and blink reflex in Friedreich's ataxia. J. Neurol 1991:238:212-6
• Durr and others. Clinical and Genetic Abnormalities in Patients with Friedreich's ataxia. NEJM 1996:335:1169-75
• Koeppen, A. H. (2011). "Friedreich's ataxia: Pathology, pathogenesis, and molecular genetics." J Neurol Sci 303(1-2): 1-12.
• Lynch, D. R., S. L. Perlman, et al. (2010). "A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia." Arch Neurol 67(8): 941-947.
• Mariotti C and others. Idebenone treatment in Friedreich patients: One-year-long randomized placebo-controlled trial. Neurology 2003: 60: 1676-79
• Moseley, M. L., K. A. Benzow, et al. (1998). "Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families." Neurology 51(6): 1666-1671.
• Velasco-Sanchez, D., A. Aracil, et al. (2011). "Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia." Cerebellum 10(1): 1-8.